An Antigenic Atlas of HIV-1 Escape from Broadly Neutralizing Antibodies Distinguishes Functional and Structural Epitopes

Dingens, Adam S.; Arenz, Dana; Weight, Haidyn; Overbaugh, Julie; Bloom, Jesse D

doi:10.1016/j.immuni.2018.12.017

Cited by 89 publications

(134 citation statements)

References 83 publications

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“…Taken together, our results identify multiple mutationally constrained patches on the RBD surface that can be targeted by antibodies. These findings provide a framework that could inform the formulation of antibody cocktails aiming to limit the emergence of viral escape mutants (Baum et al, 2020;Pinto et al, 2020;Wu et al, 2020;Zost et al, 2020), particularly if deep mutational scanning approaches like our own are extended to define RBD antibody epitopes in functional as well as structural terms (Dingens et al, 2019).…”

Section: Mutational Constraint Of Antibody Epitopesmentioning

confidence: 84%

“…Second, there are a number of RBD mutations that enhance ACE2 affinity, which implies ample evolutionary potential for compensation of deleterious mutations in the ACE2 interface in a manner reminiscent of multi-step escape pathways that have been described for other viruses (Bloom et al, 2010;Friedrich et al, 2004;Gong et al, 2013;Lynch et al, 2015;Wu et al, 2017). It should be possible to shed further experimental light on the potential for antigenic drift by extending our deep mutational scanning methodology to directly map immune-escape mutations as has been done for other viruses (Dingens et al, 2019;Lee et al, 2019;Wu et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

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Deep mutational scanning of SARS-CoV-2 receptor binding domain reveals constraints on folding and ACE2 binding

Starr

Greaney

Hilton

et al. 2020

Preprint

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615

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The receptor binding domain (RBD) of the SARS-CoV-2 spike glycoprotein mediates viral attachment to ACE2 receptor, and is a major determinant of host range and a dominant target of neutralizing antibodies. Here we experimentally measure how all amino-acid mutations to the RBD affect expression of folded protein and its affinity for ACE2. Most mutations are deleterious for RBD expression and ACE2 binding, and we identify constrained regions on the RBD's surface that may be desirable targets for vaccines and antibody-based therapeutics. But a substantial number of mutations are well tolerated or even enhance ACE2 binding, including at ACE2 interface residues that vary across SARS-related coronaviruses. However, we find no evidence that these ACE2-affinity enhancing mutations have been selected in current SARS-CoV-2 pandemic isolates. We present an interactive visualization and open analysis pipeline to facilitate use of our dataset for vaccine design and functional annotation of mutations observed during viral surveillance.

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Section: Mutational Constraint Of Antibody Epitopesmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Deep mutational scanning of SARS-CoV-2 receptor binding domain reveals constraints on folding and ACE2 binding

Starr

Greaney

Hilton

et al. 2020

Preprint

Self Cite

615

1,193

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“…Deep mutational scanning is a relatively new approach that involves creating large libraries of mutants of a gene, imposing a functional selection, and using deep sequencing to estimate the effect of every mutation from its change in frequency after selection 15 . This approach has been used to assess the effects of all viral mutations on the function and antigenicity of key proteins from influenza virus 16–18 and HIV 19,20 . Two studies have applied deep mutational scanning to ZIKV 21,22 , but these studies did not systematically map the mutational tolerance or antigenicity of all amino-acid mutations.…”

Section: Introductionmentioning

confidence: 99%

Deep mutational scanning comprehensively maps how Zika envelope protein mutations affect viral growth and antibody escape

Sourisseau

Lawrence

Schwarz

et al. 2019

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Functional constraints on viral proteins are often assessed by examining sequence conservation among natural strains, but this approach is relatively ineffective for Zika virus because all known sequences are highly similar. Here we take an alternative approach to map functional constraints on Zika virus’s envelope (E) protein by using deep mutational scanning to measure how all amino-acid mutations to the protein affect viral growth in cell culture. The resulting sequence-function map is consistent with existing knowledge about E protein structure and function, but also provides insight into mutation-level constraints in many regions of the protein that have not been well characterized in prior functional work. In addition, we extend our approach to completely map how mutations affect viral neutralization by two monoclonal antibodies, thereby precisely defining their functional epitopes. Overall, our study provides a valuable resource for understanding the effects of mutations to this important viral protein, and also offers a roadmap for future work to map functional and antigenic selection to Zika virus at high resolution. Importance Zika virus has recently been shown to be associated with severe birth defects. The virus’s E protein mediates its ability to infect cells, and is also the primary target of the antibodies that are elicited by natural infection and vaccines that are being developed against the virus. Therefore, determining the effects of mutations to this protein is important for understanding its function, its susceptibility to vaccine-mediated immunity, and its potential for future evolution. We completely mapped how amino-acid mutations to E protein affected the virus’s ability to grow in cells in the lab and escape from several antibodies. The resulting maps relate changes in the E protein’s sequence to changes in viral function, and therefore provide a valuable complement to existing maps of the physical structure of the protein.

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“…Functional characterization of env gene provides key information for vaccine design, identify env candidates capable of serving as immunogens, understanding viral evolution and pathogenesis in response to host response, or mutational landscape among several other virological and immunological functions (3–5,8,13,14). Traditionally, envelopes are characterized by generating pseudoviruses (env genes from different hosts cloned in mammalian expression vectors) in combination with env deficient HIV-1 backbones (such as PSG3∆env, ZM247∆env) (15–18).…”

Section: Introductionmentioning

confidence: 99%

A versatile high throughput strategy for cloning the env gene of HIV-1

Mishra

Sharma

Dobhal

et al. 2020

Preprint

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An Antigenic Atlas of HIV-1 Escape from Broadly Neutralizing Antibodies Distinguishes Functional and Structural Epitopes

Cited by 89 publications

References 83 publications

Deep mutational scanning of SARS-CoV-2 receptor binding domain reveals constraints on folding and ACE2 binding

Deep mutational scanning of SARS-CoV-2 receptor binding domain reveals constraints on folding and ACE2 binding

Deep mutational scanning comprehensively maps how Zika envelope protein mutations affect viral growth and antibody escape

A versatile high throughput strategy for cloning the env gene of HIV-1

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